A novel way to spread drug resistance in tumor cells: functional intercellular transfer of P-glycoprotein (ABCB1)

Abstract

Intercellular transfer of proteins is a mode of communication between cells that is crucial for certain physiological processes. Chemotherapy is the treatment of choice for approximately 50% of all cancers. However, multidrug resistance mediated by drug-efflux pumps such as P-glycoprotein (Pgp) minimizes the effectiveness of such therapy in a large number of patients. A new study demonstrates the functional intercellular transfer of Pgp. Non-genetic transfer of the multidrug resistance phenotype raises fascinating questions about the mechanism and regulation of cell-surface membrane-protein-mediated spread of traits.

Figure 1

Mechanisms for the intercellular transfer of membrane proteins: (a) exosome-mediated transfer of antigens; (b) release of glycosylphosphatidylinositol (GPI)-anchored proteins such as the prion PrP^c; (c) release of chemokine receptors such as CCR5 and CD81 on microparticles by the donor cell in response to diverse stimuli; and (d) transfer of membrane proteins through short-lived tunneling nanotubes formed on a variety of cells. Abbreviation: PKC, protein kinase C.

Figure 2

Possible ways cells can develop P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). (a) Tumor cells are either intrinsically resistant to drugs or acquire resistance on exposure to cytotoxic therapy. In both instances MDR is a consequence of the overexpression of the ABCB1 gene product. (b) Drug-sensitive (MDR⁻) cells acquire the MDR phenotype by the intercellular transfer of Pgp by an unknown mechanism but it is most probably mediated by relatively large (>0.8 μM) membrane microparticles (Figure 1c) and requires cell–cell contact with donor MDR⁺ cells [9] (for clarity only cell–cell contact is shown). It should be noted that the physiological relevance of this mechanism remains to be determined.